These Highlights Do Not Include All The Information Needed To Use Eydenzelt Safely And Effectively. See Full Prescribing Information For Eydenzelt.

Pre-filled syringe: Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after a full dose has been injected. This is normal. Do not administer any residual solution observed in the syringe.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.

Following intravitreal injection, patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17)].

Each sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new sterile, pre-filled syringe or vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYDENZELT is administered to the other eye.

After injection, any unused product must be discarded.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

Aflibercept-boav is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept-boav is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept-boav is produced in recombinant Chinese hamster ovary (CHO) cells.

EYDENZELT (aflibercept-boav) injection is a sterile, clear to slightly opalescent, and colorless to very pale brownish-yellow solution. EYDENZELT does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose, pre-filled syringe or a single-dose glass vial designed to deliver 0.05 mL of solution containing 2 mg of aflibercept-boav in histidine (0.038 mg), L-histidine monohydrochloride monohydrate (0.033 mg), polysorbate 20 (0.015 mg), sodium chloride (0.038 mg), trehalose (5 mg) and water for injection with a pH of 6.2.

Each pre-filled syringe or vial is for single eye use only. Discard unused portion. EYDENZELT injection is a clear to slightly opalescent, colorless to very pale brownish-yellow solution and is supplied in the following presentations [see Dosage and Administration (2.1), (2.2), (2.3), (2.4) and (2.8)]:

A pediatric assessment for EYDENZELT demonstrates that EYDENZELT is safe and effective for pediatric patients in an indication for which EYLEA (aflibercept) is approved. However, EYDENZELT is not approved for such indication due to marketing exclusivity for EYLEA (aflibercept).

In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with aflibercept were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of aflibercept or of other aflibercept products.

In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to aflibercept was approximately 1% to 3% across treatment groups. After dosing with aflibercept for 24-100 weeks, antibodies to aflibercept were detected in a similar percentage range of patients.

There were no differences in efficacy or safety between patients with or without immunoreactivity.

• Ocular or periocular infection (4.1)
• Active intraocular inflammation (4.2)
• Hypersensitivity (4.3)

The following potentially serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4.3)]
• Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion [see Warnings and Precautions (5.1)]
• Increase in intraocular pressure [see Warnings and Precautions (5.2)]
• Thromboembolic events [see Warnings and Precautions (5.3)]

EYDENZELT is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYDENZELT. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

Aflibercept is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of aflibercept, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).

EYDENZELT is indicated for the treatment of:

The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept products act as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Refrigerate EYDENZELT at 2°C to 8ºC (36°F to 46ºF). Do not freeze. Do not use beyond the date stamped on the carton and container label. Store in the original carton until time of use to protect from light. Do not open sealed blister pack until time of use.

There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including aflibercept products. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with aflibercept compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the aflibercept group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with aflibercept compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with aflibercept compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with aflibercept in the first six months of the RVO studies.

• Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately. (5.1)
• Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2)
• There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.3)

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.5)
  • Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2.5)
  • Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly. (2.5)
• Macular Edema Following Retinal Vein Occlusion (RVO)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly). (2.6)
• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.7, 2.8)
  • Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.7, 2.8)

EYDENZELT is a clear to slightly opalescent, colorless to very pale brownish-yellow solution available as

• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose pre-filled syringe
• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose glass vial

The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

Efficacy and safety data of aflibercept in diabetic retinopathy (DR) are derived from the VIVID, VISTA, and PANORAMA studies.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.

A total of 2980 adult patients treated with aflibercept constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with aflibercept including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 23 to 87 years with a mean of 63 years.

Of those, 576 were randomized to aflibercept groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 5 initial monthly injections (aflibercept 2Q8); 2) aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the aflibercept groups could receive laser and patients in the laser group could receive aflibercept.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both aflibercept 2Q8 and aflibercept 2Q4 groups was statistically superior to the control group. This statistically superior improvement in BCVA was maintained at week 100 in both studies.

Results from the analysis of the VIVID and VISTA studies are shown in Table 7 and Figure 17 below.

Figure 17: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 in VIVID and VISTA Studies

Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.

In the days following EYDENZELT administration, patients are at risk of developing endophthalmitis, retinal detachment, or retinal vasculitis with or without occlusion. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients and/or caregivers to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1)].

Patients may experience temporary visual disturbances after an intravitreal injection with EYDENZELT and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

EYDENZELT is contraindicated in patients with ocular or periocular infections.

EYDENZELT is contraindicated in patients with active intraocular inflammation.

For ophthalmic intravitreal injection. EYDENZELT must only be administered by a qualified physician.

Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided.

Vial: A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed.

EYDENZELT is available packaged as follows:

• Pre-filled Syringe
• Vial Kit with Injection Components (filter needle, syringe, injection needle)

[see How Supplied/Storage and Handling (16)].

Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with aflibercept products [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.4)].

EYDENZELDT should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.

The glass vial is for one-time use in one eye only.

Use aseptic technique to carry out the following preparation steps:

Prepare for intravitreal injection with the following medical devices for single use (included):

• a 5 micron sterile filter needle (18-gauge × 1 ½ inch)
• a 1 mL sterile Luer lock Syringe (with marking to measure 0.05 mL)
• a sterile injection needle (30-gauge × ½ inch)

1. Remove the protective plastic cap from the vial (see Figure 6).

Figure 6:

2. Disinfect the top of the vial with an alcohol wipe (see Figure 7).

Figure 7:

3. Remove the 18-gauge × 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 8).

Figure 8:

4. Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.

5. Using aseptic technique withdraw all of the EYDENZELDT vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid (see Figure 9).

Figure 9:

6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.

7. Remove the filter needle from the syringe and properly dispose of the filter needle.

Note: Filter needle is not to be used for intravitreal injection.

8. Remove the 30-gauge × ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 10).

Figure 10:

9. When ready to administer EYDENZELT, remove the plastic needle cap from the needle (see Figure 11).

Figure 11:

10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 12).

Figure 12:

11. To remove all of the air bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe (see Figure 13).

Figure 13:

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in adult patients after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see Clinical Studies (14)].

The EYDENZELT pre-filled syringe is sterile and for one-time use in one eye only. It should be inspected visually prior to administration. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. Do not use if any part of the pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock.

The intravitreal injection should be performed with a 30-gauge × ½-inch injection needle (not included).

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept-boav (equivalent to 0.05 mL). Discard the excess volume prior to administration.

PRE-FILLED SYRINGE DESCRIPTION – Figure 1:

1. Open the Carton.

When ready to administer EYDENZELT, open the carton and remove sterilized blister pack. Carefully peel open the sterilized blister pack ensuring the sterility of its contents. Keep the pre-filled syringe in the sterilized blister pack until you are ready for assembly.

2. Remove the Pre-filled Syringe.

Using aseptic technique, remove the pre-filled syringe from the sterilized blister pack.

3. Twist Off the Syringe Cap.

Twist off (do not snap off) the syringe cap by holding the pre-filled syringe in one hand and the syringe cap with the thumb and forefinger of the other hand (see Figure 2).

Note: To avoid compromising the sterility of the product, do not pull back on the plunger.

Figure 2:

4. Attach the Needle to the Pre-filled Syringe.

Using aseptic technique, firmly twist a 30-gauge × ½-inch injection needle onto the Luer lock syringe tip (see Figure 3).

Figure 3:

Note: When ready to administer EYDENZELT, remove the plastic needle shield from the needle.

5. Check for Air Bubbles.

Hold the pre-filled syringe with the needle pointing up and check the pre-filled syringe for bubbles (see Figure 4a). If there are bubbles, gently tap the pre-filled syringe with your finger until the bubbles rise to the top (see Figure 4b).

6. Remove Air bubbles and Set the Dose.

To remove all bubbles and to expel excess drug, SLOWLY depress the plunger rod to align the plunger dome edge (see Figure 5a) with the dosing marker shown on the barrel of the pre-filled syringe (equivalent to 0.05 mL) (see Figure 5b).

7. The pre-filled syringe is for one-time use is one eye only. After injection any unused product must be discarded.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see Clinical Studies (14.2), (14.3)].

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept products. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg.

Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free aflibercept that was approximately 1500 times higher than the systemic exposure observed in adult patients after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with aflibercept) in the two studies (VIEW1 and VIEW2). In each study, up to week 52, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 3 initial monthly doses (aflibercept 2Q8); 2) aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); 3) aflibercept 0.5 mg administered every 4 weeks (aflibercept 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Protocol-specified visits occurred every 28±3 days. Patient ages ranged from 49 to 99 years with a mean of 76 years.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Both aflibercept 2Q8 and aflibercept 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 4 and Figure 14 below.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were in general consistent with the results in the overall populations.

VIEW1 and VIEW2 studies were both 96 weeks in duration. However, after 52 weeks patients no longer followed a fixed dosing schedule. Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm.

1 Single-dose Vial (Discard unused portion)

Rx only

Eydenzelt^®

(aflibercept-boav)

Injection

2 mg (0.05 mL of

40 mg/mL solution)

FOR INTRAVITREAL INJECTION 

Each carton contains:

• one signle-dose vial of Eydenzelt (aflibercept-boav)
• one 18-gauge x 1½-inch, 5-micron, filter needle for withdrawal
  
  of the vial contents
• one 30-gauge x ½-inch injection needle for intravitreal injection
• one 1-mL syringe for administration
• one Prescribing Information 

NDC 72606-026-02

CELLTRION USA

CELLTRION

The safety and efficacy of aflibercept were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with aflibercept) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 42 to 94 years with a mean of 65 years.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint.

Detailed results from the analysis of the VIBRANT study are shown in Table 6 and Figure 16 below.

Figure 16: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study

Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with aflibercept) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 22 to 89 years with a mean of 64 years.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint.

Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 15 below.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.

Rx only

Eydenzelt^®

(aflibercept-boav)

Injection

2 mg (0.05 mL of

40 mg/mL solution)

x 1

FOR INTRAVITREAL INJECTION

One blister pack containing:

one sterile, single-dose pre-filled syringe,

one Prescribing Information

NDC 72606-026-01

CELLTRION USA

CELLTRION

Intravitreal injections, including those with aflibercept products, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with or without occlusion [see Adverse Reactions (6.2)]. Proper aseptic injection technique must always be used when administering EYDENZELT. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately [see Dosage and Administration (2.4) and Patient Counseling Information (17)].

Pre-filled syringe: Inject by pressing the plunger carefully and with constant pressure. Do not apply additional pressure once the plunger has reached the bottom of the syringe. A small residual volume may remain in the syringe after a full dose has been injected. This is normal. Do not administer any residual solution observed in the syringe.

Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.

Following intravitreal injection, patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient Counseling Information (17)].

Each sterile, pre-filled syringe or vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new sterile, pre-filled syringe or vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYDENZELT is administered to the other eye.

After injection, any unused product must be discarded.

Overdosing with increased injection volume may increase intraocular pressure. Therefore, in case of overdosage, intraocular pressure should be monitored and if deemed necessary by the treating physician, adequate treatment should be initiated.

Aflibercept-boav is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept-boav is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept-boav is produced in recombinant Chinese hamster ovary (CHO) cells.

EYDENZELT (aflibercept-boav) injection is a sterile, clear to slightly opalescent, and colorless to very pale brownish-yellow solution. EYDENZELT does not contain anti-microbial preservative and is supplied as a sterile, aqueous solution for intravitreal injection in a single-dose, pre-filled syringe or a single-dose glass vial designed to deliver 0.05 mL of solution containing 2 mg of aflibercept-boav in histidine (0.038 mg), L-histidine monohydrochloride monohydrate (0.033 mg), polysorbate 20 (0.015 mg), sodium chloride (0.038 mg), trehalose (5 mg) and water for injection with a pH of 6.2.

Each pre-filled syringe or vial is for single eye use only. Discard unused portion. EYDENZELT injection is a clear to slightly opalescent, colorless to very pale brownish-yellow solution and is supplied in the following presentations [see Dosage and Administration (2.1), (2.2), (2.3), (2.4) and (2.8)]:

A pediatric assessment for EYDENZELT demonstrates that EYDENZELT is safe and effective for pediatric patients in an indication for which EYLEA (aflibercept) is approved. However, EYDENZELT is not approved for such indication due to marketing exclusivity for EYLEA (aflibercept).

In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with aflibercept were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of aflibercept or of other aflibercept products.

In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to aflibercept was approximately 1% to 3% across treatment groups. After dosing with aflibercept for 24-100 weeks, antibodies to aflibercept were detected in a similar percentage range of patients.

There were no differences in efficacy or safety between patients with or without immunoreactivity.

• Ocular or periocular infection (4.1)
• Active intraocular inflammation (4.2)
• Hypersensitivity (4.3)

The following potentially serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4.3)]
• Endophthalmitis, Retinal Detachments, and Retinal Vasculitis with or without Occlusion [see Warnings and Precautions (5.1)]
• Increase in intraocular pressure [see Warnings and Precautions (5.2)]
• Thromboembolic events [see Warnings and Precautions (5.3)]

EYDENZELT is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYDENZELT. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.

Aflibercept is administered intravitreally to exert local effects in the eye. In patients with wet AMD, RVO, or DME, following intravitreal administration of aflibercept, a fraction of the administered dose is expected to bind with endogenous VEGF in the eye to form an inactive aflibercept: VEGF complex. Once absorbed into the systemic circulation, aflibercept presents in the plasma as free aflibercept (unbound to VEGF) and a more predominant stable inactive form with circulating endogenous VEGF (i.e., aflibercept: VEGF complex).

EYDENZELT is indicated for the treatment of:

The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leucocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability.

Aflibercept products act as a soluble decoy receptor that binds VEGF-A and PlGF, and thereby can inhibit the binding and activation of these cognate VEGF receptors.

Refrigerate EYDENZELT at 2°C to 8ºC (36°F to 46ºF). Do not freeze. Do not use beyond the date stamped on the carton and container label. Store in the original carton until time of use to protect from light. Do not open sealed blister pack until time of use.

There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including aflibercept products. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with aflibercept compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the aflibercept group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with aflibercept compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with aflibercept compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with aflibercept in the first six months of the RVO studies.

• Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately. (5.1)
• Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2)
• There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.3)

• Neovascular (Wet) Age-Related Macular Degeneration (AMD)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 3 months, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.5)
  • Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). (2.5)
  • Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly. (2.5)
• Macular Edema Following Retinal Vein Occlusion (RVO)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly). (2.6)
• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)
  • The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). (2.7, 2.8)
  • Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months). (2.7, 2.8)

EYDENZELT is a clear to slightly opalescent, colorless to very pale brownish-yellow solution available as

• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose pre-filled syringe
• Injection: 2 mg (0.05 mL of a 40 mg/mL solution) in a single-dose glass vial

The following adverse reactions have been identified during postapproval use of aflibercept. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.5)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

Efficacy and safety data of aflibercept in diabetic retinopathy (DR) are derived from the VIVID, VISTA, and PANORAMA studies.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.

A total of 2980 adult patients treated with aflibercept constituted the safety population in eight phase 3 studies. Among those, 2379 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with aflibercept including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving aflibercept were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.4)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks (5 months).

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, controlled studies in patients with DME. A total of 862 randomized and treated patients were evaluable for efficacy. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 23 to 87 years with a mean of 63 years.

Of those, 576 were randomized to aflibercept groups in the two studies (VIVID and VISTA). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 5 initial monthly injections (aflibercept 2Q8); 2) aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); and 3) macular laser photocoagulation (at baseline and then as needed). Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the aflibercept groups could receive laser and patients in the laser group could receive aflibercept.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at week 52 as measured by ETDRS letter score. Efficacy of both aflibercept 2Q8 and aflibercept 2Q4 groups was statistically superior to the control group. This statistically superior improvement in BCVA was maintained at week 100 in both studies.

Results from the analysis of the VIVID and VISTA studies are shown in Table 7 and Figure 17 below.

Figure 17: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 100 in VIVID and VISTA Studies

Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study were in general consistent with the results in the overall populations.

In the days following EYDENZELT administration, patients are at risk of developing endophthalmitis, retinal detachment, or retinal vasculitis with or without occlusion. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients and/or caregivers to seek immediate care from an ophthalmologist [see Warnings and Precautions (5.1)].

Patients may experience temporary visual disturbances after an intravitreal injection with EYDENZELT and the associated eye examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

EYDENZELT is contraindicated in patients with ocular or periocular infections.

EYDENZELT is contraindicated in patients with active intraocular inflammation.

For ophthalmic intravitreal injection. EYDENZELT must only be administered by a qualified physician.

Pre-filled Syringe: A 30-gauge × ½-inch sterile injection needle is needed but not provided.

Vial: A 5-micron sterile filter needle (18-gauge × 1½-inch), a 1-mL Luer lock syringe and a 30-gauge × ½-inch sterile injection needle are needed.

EYDENZELT is available packaged as follows:

• Pre-filled Syringe
• Vial Kit with Injection Components (filter needle, syringe, injection needle)

[see How Supplied/Storage and Handling (16)].

Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with aflibercept products [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration (2.4)].

EYDENZELDT should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used.

The glass vial is for one-time use in one eye only.

Use aseptic technique to carry out the following preparation steps:

Prepare for intravitreal injection with the following medical devices for single use (included):

• a 5 micron sterile filter needle (18-gauge × 1 ½ inch)
• a 1 mL sterile Luer lock Syringe (with marking to measure 0.05 mL)
• a sterile injection needle (30-gauge × ½ inch)

1. Remove the protective plastic cap from the vial (see Figure 6).

Figure 6:

2. Disinfect the top of the vial with an alcohol wipe (see Figure 7).

Figure 7:

3. Remove the 18-gauge × 1½-inch, 5-micron, filter needle and the 1-mL syringe from their packaging. Attach the filter needle to the syringe by twisting it onto the Luer lock syringe tip (see Figure 8).

Figure 8:

4. Push the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or bottom edge of the vial.

5. Using aseptic technique withdraw all of the EYDENZELDT vial contents into the syringe, keeping the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the liquid (see Figure 9).

Figure 9:

6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to completely empty the filter needle.

7. Remove the filter needle from the syringe and properly dispose of the filter needle.

Note: Filter needle is not to be used for intravitreal injection.

8. Remove the 30-gauge × ½-inch injection needle from its packaging and attach the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip (see Figure 10).

Figure 10:

9. When ready to administer EYDENZELT, remove the plastic needle cap from the needle (see Figure 11).

Figure 11:

10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 12).

Figure 12:

11. To remove all of the air bubbles and to expel excess drug, SLOWLY depress the plunger so that the plunger tip aligns with the line that marks 0.05 mL on the syringe (see Figure 13).

Figure 13:

Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at intravitreal doses of 2 or 4 mg per eye. At the NOAEL of 0.5 mg per eye in monkeys, the systemic exposure (AUC) was 56 times higher than the exposure observed in adult patients after an intravitreal dose of 2 mg. Similar effects were not seen in clinical studies [see Clinical Studies (14)].

The EYDENZELT pre-filled syringe is sterile and for one-time use in one eye only. It should be inspected visually prior to administration. Do not use if particulates, cloudiness, or discoloration are visible, or if the package is open or damaged. Do not use if any part of the pre-filled syringe is damaged or if the syringe cap is detached from the Luer lock.

The intravitreal injection should be performed with a 30-gauge × ½-inch injection needle (not included).

The pre-filled syringe contains more than the recommended dose of 2 mg aflibercept-boav (equivalent to 0.05 mL). Discard the excess volume prior to administration.

PRE-FILLED SYRINGE DESCRIPTION – Figure 1:

1. Open the Carton.

When ready to administer EYDENZELT, open the carton and remove sterilized blister pack. Carefully peel open the sterilized blister pack ensuring the sterility of its contents. Keep the pre-filled syringe in the sterilized blister pack until you are ready for assembly.

2. Remove the Pre-filled Syringe.

Using aseptic technique, remove the pre-filled syringe from the sterilized blister pack.

3. Twist Off the Syringe Cap.

Twist off (do not snap off) the syringe cap by holding the pre-filled syringe in one hand and the syringe cap with the thumb and forefinger of the other hand (see Figure 2).

Note: To avoid compromising the sterility of the product, do not pull back on the plunger.

Figure 2:

4. Attach the Needle to the Pre-filled Syringe.

Using aseptic technique, firmly twist a 30-gauge × ½-inch injection needle onto the Luer lock syringe tip (see Figure 3).

Figure 3:

Note: When ready to administer EYDENZELT, remove the plastic needle shield from the needle.

5. Check for Air Bubbles.

Hold the pre-filled syringe with the needle pointing up and check the pre-filled syringe for bubbles (see Figure 4a). If there are bubbles, gently tap the pre-filled syringe with your finger until the bubbles rise to the top (see Figure 4b).

6. Remove Air bubbles and Set the Dose.

To remove all bubbles and to expel excess drug, SLOWLY depress the plunger rod to align the plunger dome edge (see Figure 5a) with the dosing marker shown on the barrel of the pre-filled syringe (equivalent to 0.05 mL) (see Figure 5b).

7. The pre-filled syringe is for one-time use is one eye only. After injection any unused product must be discarded.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see Clinical Studies (14.2), (14.3)].

No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept products. Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at weekly doses ranging from 3 to 30 mg per kg.

Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. In addition, females showed decreased ovarian and uterine weight accompanied by compromised luteal development and reduction of maturing follicles. These changes correlated with uterine and vaginal atrophy. A No Observed Adverse Effect Level (NOAEL) was not identified. Intravenous administration of the lowest dose of aflibercept assessed in monkeys (3 mg per kg) resulted in systemic exposure (AUC) for free aflibercept that was approximately 1500 times higher than the systemic exposure observed in adult patients after an intravitreal dose of 2 mg. All changes were reversible within 20 weeks after cessation of treatment.

The recommended dose for EYDENZELT is 2 mg (0.05 mL of 40 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL of 40 mg/mL solution) via intravitreal injection once every 8 weeks (2 months). Although EYDENZELT may be dosed as frequently as 2 mg every 4 weeks (approximately every 25 days, monthly), additional efficacy was not demonstrated in most patients when aflibercept was dosed every 4 weeks compared to every 8 weeks [see Clinical Studies (14.1)]. Some patients may need every 4 week (monthly) dosing after the first 12 weeks (3 months). Although not as effective as the recommended every 8 week dosing regimen, patients may also be treated with one dose every 12 weeks after one year of effective therapy. Patients should be assessed regularly.

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, active-controlled studies in patients with wet AMD. A total of 2412 patients were treated and evaluable for efficacy (1817 with aflibercept) in the two studies (VIEW1 and VIEW2). In each study, up to week 52, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: 1) aflibercept administered 2 mg every 8 weeks following 3 initial monthly doses (aflibercept 2Q8); 2) aflibercept administered 2 mg every 4 weeks (aflibercept 2Q4); 3) aflibercept 0.5 mg administered every 4 weeks (aflibercept 0.5Q4); and 4) ranibizumab administered 0.5 mg every 4 weeks (ranibizumab 0.5 mg Q4). Protocol-specified visits occurred every 28±3 days. Patient ages ranged from 49 to 99 years with a mean of 76 years.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at week 52 compared to baseline. Both aflibercept 2Q8 and aflibercept 2Q4 groups were shown to have efficacy that was clinically equivalent to the ranibizumab 0.5 mg Q4 group in year 1.

Detailed results from the analysis of the VIEW1 and VIEW2 studies are shown in Table 4 and Figure 14 below.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were in general consistent with the results in the overall populations.

VIEW1 and VIEW2 studies were both 96 weeks in duration. However, after 52 weeks patients no longer followed a fixed dosing schedule. Between week 52 and week 96, patients continued to receive the drug and dosage strength to which they were initially randomized on a modified 12 week dosing schedule (doses at least every 12 weeks and additional doses as needed). Therefore, during the second year of these studies there was no active control comparison arm.

1 Single-dose Vial (Discard unused portion)

Rx only

Eydenzelt^®

(aflibercept-boav)

Injection

2 mg (0.05 mL of

40 mg/mL solution)

FOR INTRAVITREAL INJECTION 

Each carton contains:

• one signle-dose vial of Eydenzelt (aflibercept-boav)
• one 18-gauge x 1½-inch, 5-micron, filter needle for withdrawal
  
  of the vial contents
• one 30-gauge x ½-inch injection needle for intravitreal injection
• one 1-mL syringe for administration
• one Prescribing Information 

NDC 72606-026-02

CELLTRION USA

CELLTRION

The safety and efficacy of aflibercept were assessed in a 24-week, randomized, multi-center, double-masked, controlled study in patients with macular edema following BRVO. A total of 181 patients were treated and evaluable for efficacy (91 with aflibercept) in the VIBRANT study. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4) or laser photocoagulation administered at baseline and subsequently as needed (control group). Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 42 to 94 years with a mean of 65 years.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint.

Detailed results from the analysis of the VIBRANT study are shown in Table 6 and Figure 16 below.

Figure 16: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 24 in VIBRANT Study

Treatment effects in evaluable subgroups (e.g., age, gender, and baseline retinal perfusion status) in the study were in general consistent with the results in the overall populations.

The safety and efficacy of aflibercept were assessed in two randomized, multi-center, double-masked, sham-controlled studies in patients with macular edema following CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with aflibercept) in the two studies (COPERNICUS and GALILEO). In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg aflibercept administered every 4 weeks (2Q4), or sham injections (control group) administered every 4 weeks for a total of 6 injections. Protocol-specified visits occurred every 28±7 days. Patient ages ranged from 22 to 89 years with a mean of 64 years.

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA compared to baseline. At week 24, the aflibercept 2 mg Q4 group was superior to the control group for the primary endpoint.

Results from the analysis of the COPERNICUS and GALILEO studies are shown in Table 5 and Figure 15 below.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity, retinal perfusion status, and CRVO duration) in each study and in the combined analysis were in general consistent with the results in the overall populations.

Rx only

Eydenzelt^®

(aflibercept-boav)

Injection

2 mg (0.05 mL of

40 mg/mL solution)

x 1

FOR INTRAVITREAL INJECTION

One blister pack containing:

one sterile, single-dose pre-filled syringe,

one Prescribing Information

NDC 72606-026-01

CELLTRION USA

CELLTRION

Intravitreal injections, including those with aflibercept products, have been associated with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)] and, more rarely, retinal vasculitis with or without occlusion [see Adverse Reactions (6.2)]. Proper aseptic injection technique must always be used when administering EYDENZELT. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately [see Dosage and Administration (2.4) and Patient Counseling Information (17)].